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IKK[beta] deficiency causes oxidative stress and prolonged JNK activation induced by arsenic.

Authors
Chen-F; Castranova-V; Li-ZW; Karin-M; Shi-XL
Source
Free Radic Biol Med 2003 Nov; 35(Suppl 1):S61-S62
NIOSHTIC No.
20032105
Abstract
Stress signals activate both IkB kinase (IKK) and c-Jun-Nterminal kinase (JNK), Recently, it was shown that IKK dependent NF-kB activation results in attenuation of TNFalpha-induced JNK activation. How that negative cross-talk between NF-kB and JNK occurs is not well-understood. By using wild type (WT) and Ikkbeta gene knockout (lkkB-/- ) mouse embryo fibroblasts (MEFs), we found that IKKB deficiency results in prolongation of arsenic-induced JNK activation, which was not due to the decreased expression of GADD45B or XIAP. as previously suggested for ReIA -/- cells treated with TNFalpha. This enhanced JNK activation was largely associated with an oxidative stress response as indicated by elevated expression of heme oxygenase-l and the accumulation of H2O2 in IkkB-/- cells. Expression profiling experiments revealed an increased expression of p450 family CYP1B1 mRNA in IkkB-/- cells compared to WT cells. Inhibition of CYP1B1 reduced both oxidative stress and arsenic-stimulated JNK activation. Thus, increased CYP1B1 expression is central to and seems to be responsible for sensitizing IkkB-/- cells to stress-induced JNK activation.
Keywords
Biochemical-analysis; Molecular-biology; Arsenic-compounds; Genes; Cell-function; Cellular-reactions; Oxidative-processes; Laboratory-animals; Animal-studies; Hydroperoxides
Contact
National Institute for Occupational Safety and Health, Health Effects Laboratory Division, Pathology and Physiological Research Branch, 1095 Willowdale Road, Morgantown, WV 26505
CODEN
FRBMEH
CAS No.
7440-38-2; 7722-84-1
Publication Date
20031120
Document Type
Abstract; Conference/Symposia Proceedings
Fiscal Year
2004
NTIS Accession No.
NTIS Price
ISSN
0891-5849
NIOSH Division
HELD
Source Name
Free Radical Biology and Medicine
State
WV; CA
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